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PubMed1977

A comparative study on the influence of cysteamine and metyrapone on mixed-function oxygenase activities in variously pretreated liver microsomes from rats and mice.

It has been found that metyrapone can inhibit both type I and type II mixed-function oxygenase reactions, while cysteamine inhibits only type I activity in this mammalian system. Following pretreatment with phenobarbital and 3-methylcholanthrene the half-maximal inhibiting concentrations for the O-demethylation of paranitranisol are increased for cysteamine and decreased for metyrapone. Both cysteamine and metyrapone give type II binding spectra with oxidized cytochrome P-450. The negative and positive peaks are at 393 and 426 nm respectively for metyrapone, and 410 and 434 nm for cysteamine. Cysteamine showed no binding comparable to that of metyrapone for reduced cytochrome P-450. Metyrapone showed little or no inhibition of the NADH cytochrome-c reductase (EC 1.6.1.1) or NADPH (EC 1.6.2.3) cytochrome-c reductase while cysteamine had a more or less strong inhibiting effect depending on the pretreatment of animals. Neither the binding to P-450 heme nor the inhibition of NADH and NADPH cytochrome-c reductase correlates well with cysteamine inhibition of total activity. It is therefore suggested that cysteamine reacts with an intermediate electron carrier of non-heme iron or glycoprotein character thus inhibiting mixed-function oxygenase activity.

Acetanilides↗
PubMed1996

Characterization of the in vivo inhibition of rat hepatic microsomal aldehyde dehydrogenase activity by metyrapone.

Microsomal aldehyde dehydrogenase (mALDH; EC 1.2.1.3) has been proposed to catalyze the oxidation of various aldehydic products of lipid peroxidation, but the regulation of the enzyme has not been characterized. Metyrapone administration (100 mg/kg, i.p.) produced a rapid decline in the rates of mALDH-catalyzed decanal dehydrogenation; other xenobiotics were generally without effect. Thus, a 22% decrease in activity was detected 2 hr following metyrapone administration, and 52% of the activity remained at 6 hr. The decrease in microsomal decanal dehydrogenation was also dose-dependent with 70, 43, and 12% of the control activity remaining following pretreatment with 25, 100, and 250 mg/kg metyrapone, respectively. This disease in microsomal decanal dehydrogenase activity occurred without a change in mALDH immunoreactive protein, and metyrapone did not inhibit the activity in vitro. The kinetic analysis revealed similar decreases in the maximal reaction velocities (Vmax) for both decanal and NAD in the metyrapone-treated group (200 +/- 10 and 190 +/- 20 nmol NADH produced/min/mg protein, respectively) compared with the untreated group (330 +/- 10 and 350 +/- 20 nmol NADH produced/min/mg protein, respectively), but the Michaelis constants (Km) were unchanged. These data are consistent with the in vivo inactivation of a portion of the mALDH enzyme. A possible consequence of the in vivo inhibition of this enzyme by metyrapone could be the accumulation of toxic aldehydes in the vicinity of the microsomal membrane following lipid peroxidation.

Aldehyde Dehydrogenase↗
PubMed1996

The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles.

In order to investigate mechanisms by which the adrenal 11 beta-hydroxylase inhibitor metyrapone might exert its antidepressant effect, we used gas chromatography to analyse the 24 h urinary steroid profiles from six females with major depression taking part in a trial of metyrapone (2-4 g/day) as an antidepressant. Due to concurrent administration of hydrocortisone (30 mg/day), plasma cortisol levels were not significantly reduced. Treatment with metyrapone resulted in greatly increased urinary excretion of 11-deoxy corticosteroids, including the GABA-modulatory steroid tetrahydro-11-deoxycorticosterone (from 68 +/- 34 to 219 +/- 75 micrograms/24 h, p < .05). Metyrapone also had multiple extra-adrenal effects on corticosteroid metabolism, including inhibition of the peripheral conversion of cortisone to cortisol as demonstrated by a significant decrease in the ratio of 11 beta-hydroxy/11-oxo metabolites of cortisol (from 0.81 +/- 0.08 to 0.46 +/- 0.04, p < .01). The decreased Montgomery-Asberg Depression Rating Scale scores seen during treatment with metyrapone did not correlate with changes in plasma cortisol, but did correlate significantly with total 11-deoxycortisol metabolites (r = 0.778, n = 12, p < .01). We conclude that, in addition to decreased cortisol synthesis, increased secretion of cortisol precursors and reduced local bioavailability of cortisol may play a role in the antidepressant effect of metyrapone.

Adult↗
PubMed2005

Metyrapone and cocaine: a double-blind, placebo-controlled drug interaction study.

Pre-clinical research suggests that suppression of adrenocorticosteroid synthesis might decrease susceptibility to stress-induced relapse. Metyrapone effectively suppresses cortisol synthesis and thus might have promise as a cocaine dependence treatment. The present inpatient study evaluated the interaction of metyrapone and cocaine to assess the safety of conducting an outpatient trial. Twelve nontreatment-seeking cocaine-dependent individuals completed this double-blind, placebo-controlled, crossover study with two factors: medication (750 mg of metyrapone vs. placebo) and infusion (40 mg of cocaine vs. saline). Safety measures included vital signs, adverse events, and electrocardiogram. Efficacy measures included visual analog scale (VAS) ratings of craving and drug effect. Neuroendocrine measures included cortisol and ACTH. As predicted, metyrapone was well tolerated and did not exacerbate cocaine's physiological effects. Also as predicted, metyrapone did not significantly alter cocaine's subjective effects. The results of the present study suggest that metyrapone at the dose studied can likely be used safely in an outpatient study with active cocaine users.

Adolescent↗
PubMed2003

11beta-Hydroxysteroid dehydrogenase type 1: tissue-specific expression and reductive metabolism of some anti-insect agent azole analogues of metyrapone.

The azole analogues of metyrapone are novel candidates for selective anti-insect agents that inhibit the synthesis of 20-hydroxyecdysone (20E), the moulting hormone of insects. Metyrapone, which is a model substrate for studying the reductive properties of oxidoreductases, is itself effectively reduced to the corresponding alcohol by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1). For this reason, the ability of 11beta-HSD 1 to metabolize the metyrapone analogues as well was studied. In addition, the expression (by Western blots) and activity (reduction/oxidation of dehydrocorticosterone/corticosterone) of 11beta-HSD 1 in different male and female mouse tissues were investigated. Xenobiotic carbonyl reductase activities in these tissues were assessed with metyrapone as a model substrate. The kinetic parameters of 11beta-HSD 1 with metyrapone analogues as substrates were calculated after high-pressure liquid chromatography (HPLC) determination of the product alcohols. Our results indicate that the novel insecticides are extensively metabolized by mouse 11beta-HSD 1. Moreover, the resulting alcohols are not only less toxic than the parent ketones but also have the potential, owing to the newly formed hydroxyl group, to be eliminated from the body by consecutive phase II reactions. Thus, the new metyrapone analogues may be potential anti-insect agents, safer for humans due to their reductive detoxification, mainly by the hepatic 11beta-HSD 1, and selectively affecting insect development by inhibiting ecdysone 20-monooxygenase (E-20-M).

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Metyrapone alleviates ischemic neuronal damage in the gerbil hippocampus.

Transient forebrain ischemia was induced in gerbils, and the effect of a pre-ischemic treatment with metyrapone (100 mg/kg) on delayed neuronal death in hippocampal CA1 neurons was evaluated. The effect of metyrapone on the ischemic release of amino acids in the CA1 region was also examined by microdialysis. Hippocampal slices were used for the evaluation of the hypoxia-induced intracellular Ca2+ increase by microfluorometry. The metyrapone treatment morphologically improved the damage provoked by 3 min of ischemia, although it did not alleviate the damage by 5 min. Ischemia for 3 min produced a 306% increase in the glutamate concentration in perfusates, and metyrapone suppressed the peak value to 42% of that in the control group. The extent of the increase in fluorescence intensity by intracellular Ca2+ was lower by 16% in slices from metyrapone-treated animals than in controls 600 s after induction of hypoxia. The removal of Ca2+ from the perfusion medium suppressed the hypoxic Ca2+ increase, and the increase was further reduced in slices pretreated with metyrapone. The increase in the level of endogenous glucocorticoids, which occurs in cerebral ischemia, may aggravate ischemic neuronal damage.

Amino Acids↗
PubMed1983

Cytochrome P-450 isozyme 1 from phenobarbital-induced rat liver: purification, characterization, and interactions with metyrapone and cytochrome b5.

Cytochrome P-450 isozyme 1 (PB-1) (Mr congruent to 53 000) was purified to apparent homogeneity from phenobarbital (PB)-induced rat liver microsomes, and its spectral, structural, immunochemical, and catalytic properties were determined. PB-1, present in significant amounts in uninduced rat liver microsomes, is induced approximately 2-4-fold by phenobarbital, as compared to the greater than 30-fold induction typical of the major PB isozymes characterized previously. PB-1 was distinguished from the major PB-induced isozymes PB-4 and PB-5 [Waxman, D. J., & Walsh, C. (1982) J. Biol. Chem. 257, 10446-10457] by the absence of a Fe2+-metyrapone P446 complex, by its unique NH2-terminal sequence and distinct peptide maps, by the lack of immuno-cross-reactivity to PB-4, and by its characteristic substrate-specificity profile. Metyrapone effected a saturable enhancement of several PB-1-catalyzed reactions in the reconstituted system [Km(metyrapone) congruent to 200 microM], which varied in magnitude with the substrate, with a maximal stimulation of 5-8-fold in the case of acetanilide 4-hydroxylation. That metyrapone enhanced the corresponding microsomal activities only in cases where the metyrapone-sensitive PB-4 did not catalyze the same reaction at significant rates suggested that PB-1 is probably responsible for the substrate-dependent stimulatory effects of metyrapone on microsomal monooxygenations. In contrast to PB-4 and PB-5, PB-1 was characterized by a marked, but not absolute, dependence on cytochrome b5 (b5) for catalytic activity, with 4-7-fold stimulations typically effected by inclusion of stoichiometric b5 in the reconstituted system. That these b5-stimulations were lipid dependent and were abolished with specific proteolytic fragments lacking b5's COOH-terminal membranous segment evidenced the importance of this segment for efficient, b5-mediated electron transfer to P-450 PB-1 in the reconstituted monooxygenase system.

Amino Acid Sequence↗
PubMed1977

New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.

A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.

Adrenal Cortex↗
PubMed1996

A comparison of the overnight and the standard metyrapone test for the differential diagnosis of adrenocorticotrophin-dependent Cushing's syndrome.

OBJECTIVE: We wished to develop optimal criteria for interpreting the single-dose overnight metyrapone test and to compare the diagnostic efficiency of the overnight and the standard 6-dose metyrapone tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. DESIGN: Retrospective pilot study based on all patients who completed both metyrapone tests and whose diagnoses were subsequently confirmed surgically. PATIENTS: Sixty-three patients, 57 with pituitary tumours and 6 with ectopic ACTH syndrome, were studied. MEASUREMENTS: The sensitivity and specificity were determined using stimulation of plasma 11-deoxycortisol and suppression of plasma cortisol as endpoints for the overnight test and stimulation of urine 17-hydroxysteroid and plasma 11-deoxycortisol as endpoints for the standard test. The lest response that gave the highest sensitivity for the diagnosis of Cushing's disease, with 100% specificity, was determined for each test endpoint. RESULTS: Both the stimulation of plasma 11-deoxycortisol and the suppression of plasma cortisol were expressed as the ratio of the post-metyrapone value to baseline. A plasma 11-deoxycortisol ratio > than 220 or a plasma cortisol ratio > 0.6 was associated with 100% specificity for diagnosis of Cushing's disease by the overnight test. When these two criteria were combined, the sensitivity was 65%, which was significantly higher than that obtained using either steroid alone: 42% for both plasma 11-deoxycortisol and plasma cortisol. The sensitivity of 65% for the overnight test, at 100% specificity, was nearly identical to that of the standard test in the same patients: 67% for the combined criterion of > 70% stimulation of urine 17-hydroxysteroid or > 480-fold increase of plasma 11-deoxycortisol. When the criteria for both the overnight and standard tests were combined, the sensitivity increased to 84%, which was higher than that obtained using the criteria for either test alone (P < 0.02). CONCLUSION: The single-dose overnight metyrapone test, which can be performed in 24 hours and which avoids the disadvantages associated with timed urine collections, has a nearly identical sensitivity (for a specificity of 100%) as the 6-dose standard metyrapone test for the diagnosis of Cushing's disease. Furthermore, the diagnostic performance of a criterion that combines the results of both tests is significantly better than the best criterion for either test alone.

ACTH Syndrome, Ectopic↗
PubMed2003

Sleep endocrine effects of the 11-beta-hydroxysteroiddehydrogenase inhibitor metyrapone.

STUDY OBJECTIVES: Besides regulating hormone secretion, steroids also modulate sleep architecture in specific ways. To simulate a state of altered glucocorticoid- and mineralocorticoid-receptor occupation, we administered metyrapone, an 11-beta-hydroxylase inhibitor, that blocks adrenal cortisol synthesis and inhibits the 11-beta-hydroxysteroiddehydrogenase type-1 enzyme in the central nervous system and investigated endocrine changes and the sleep electroencephalogram. DESIGN: Each volunteer spent 4 nights in the sleep laboratory, the first of which served to habituate the subject to the conditions in the laboratory. The volunteers underwent 3 trial conditions in random order and in a single-blind design receiving 2 doses of metyrapone (4.5 g or 6.0 g) or placebo on the day before the sleep electroencephalogram recordings. SETTING: Sleep laboratory. PARTICIPANTS: 8 healthy male volunteers. MEASUREMENTS AND RESULTS: The corticotropin secretion was significantly enhanced by metyrapone, while the cortisol secretion remained largely unchanged. Growth hormone, progesterone, and dehydroepiandrosterone concentrations were also significantly increased by both doses. Metyrapone induced a pronounced reduction in slow-wave sleep and had slight but nonlinear effects upon rapid eye movement sleep. Parameters of sleep quality were not different between groups. CONCLUSIONS: Metyrapone induces pronounced effects on hormonal secretion and the sleep electroencephalogram. These results are in part comparable to those from experiments with the administration of corticotropin-releasing hormone and with experiments that deplete mineralocorticoid receptors. The findings may be explained by altered steroid synthesis proximal to the enzyme block. Metyrapone exerts not only effects upon adrenocortical steroid synthesis, but also important extra-adrenal effects on central corticosteroid metabolism.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1996

Metyrapone, an inhibitor of glucocorticoid production, reduces brain injury induced by focal and global ischemia and seizures.

Increasing evidence indicates that glucocorticoids (GCs), produced in response to physical/emotional stressors, can exacerbate brain damage resulting from cerebral ischemia and severe seizure activity. However, much of the supporting evidence has come from studies employing nonphysiological paradigms in which adrenalectomized rats were compared with those exposed to constant GC concentrations in the upper physiological range. Cerebral ischemia and seizures can induce considerable GC secretion. We now present data from experiments using metyrapone (an 11-beta-hydroxylase inhibitor of GC production), which demonstrate that the GC stress-response worsens subsequent brain damage induced by ischemia and seizures in rats. Three different paradigms of brain injury were employed: middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia; four-vessel occlusion (4VO) model of transient global forebrain ischemia; and kainic acid (KA)-induced (seizure-mediated) excitotoxic damage to hippocampal CA3 and CA1 neurons. Metyrapone (200 mg/kg body wt) was administered systemically in a single i.p. bolus 30 min prior to each insult. In the MCAO model, metyrapone treatment significantly reduced infarct volume and also preserved cells within the infarct. In the 4VO model, neuronal loss in region CA1 of the hippocampus was significantly reduced in rats administered metyrapone. Seizure-induced damage to hippocampal pyramidal neurons (assessed by cell counts and immunochemical analyses of cytoskeletal alterations) was significantly reduced in rats administered metyrapone. Measurement of plasma levels of corticosterone (the species-typical GC of rats) after each insult showed that metyrapone significantly suppressed the injury-induced rise in levels of circulating corticosterone. These findings indicate that endogenous corticosterone contributes to the basal level of brain injury resulting from cerebral ischemia and excitotoxic seizure activity and suggest that drugs that suppress glucocorticoid production may be effective in reducing brain damage in stroke and epilepsy patients.

Animals↗
PubMed1998

Metyrapone reduces rat brain damage and seizures after hypoxia-ischemia: an effect independent of modulation of plasma corticosterone levels?

Hypoxia-ischemia is accompanied by abundant corticosterone secretion that could exacerbate brain damage after the insult. The authors demonstrate that the steroid synthesis inhibitor metyrapone (150 mg/kg subcutaneously) suppresses the hypoxia-ischemia-induced rise of plasma corticosterone levels (17.3 +/- 3.6 micrograms/dL) when compared with corticosterone-treated animals (72.2 +/- 4.8 micrograms/dL) immediately after hypoxia-ischemia. In parallel, metyrapone reduced brain damage (P < 0.05). Moreover, none of the metyrapone-treated animals displayed seizures, whereas seven of eight corticosterone-treated animals had seizures after hypoxia-ischemia. Although corticosterone administration in metyrapone-treated animals elevated plasma corticosterone levels (39.0 +/- 5.3 micrograms/dL), this did not result in a subsequent increase in brain damage and seizures when compared with metyrapone-treated animals. The authors conclude that metyrapone reduces brain damage and the incidence of seizures after hypoxia-ischemia but that this effect might partially be independent from its effect on modulating plasma corticosterone levels.

Animals↗
PubMed1990

Metyrapone-induced withdrawal symptoms.

The metyrapone test is widely used in endocrinological testing to assess the integrity of hypothalamic-pituitary-adrenal axis function; we have used it to study the metabolic basis of addictive disease and opioid dependence. In recent studies, we have observed that metyrapone administration in long-term methadone-maintained patients and in patients undergoing slow dose reduction to drug-free status following chronic treatment may induce a narcotic withdrawal-like syndrome. Although metyrapone is known to produce mild adverse reactions in non-opiate dependent subjects, narcotic withdrawal-like symptoms have not been previously observed or reported. The metyrapone test was administered to 15 former heroin addicts: 10 (8 male, 2 female) in steady-state methadone maintenance therapy (30 to 90 mg/d) and 5 (3 male, 2 female) in the final phase of a slow methadone dose reduction procedure (0 to 10 mg/d). Eight out of 15 methadone maintenance subjects exhibited a narcotic withdrawal-like syndrome ranging from 'moderate' to 'severe' and four additional subjects had 'mild' symptoms, occurring within 1 h after metyrapone administration, and resolving within 2 h of onset. No significant symptoms were seen in 3 methadone maintained subjects nor in any of 9 normal volunteers (7 male, 2 female). The mechanism by which metyrapone induces symptoms resembling narcotic withdrawal in opiate-dependent individuals is unknown but physicians performing this test should be aware of this possible response.

Adult↗
PubMed1995

Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency.

BACKGROUND AND OBJECTIVE: Previous studies suggesting effects of metyrapone on extra-adrenal corticosteroid metabolism have involved significant alterations in plasma cortisol. We have therefore studied effects of metyrapone on urinary excretion of steroids in a group of patients treated concurrently with hydrocortisone so that changes in plasma cortisol were minimized. DESIGN: Replacement doses of hydrocortisone (30 mg/day) were given concurrently with metyrapone (2-4 g/day) for 2 weeks. Blood samples were taken and 24-hour urinary steroid collections were made at baseline and after 1 and 2 weeks of treatment. PATIENTS: Subjects were 6 female patients with major depression from a trial of metyrapone as an antidepressant. MEASUREMENTS: Urinary steroid profiles were measured by gas chromatography; plasma cortisol and urinary free cortisol were measured by fluorescence immunoassay. RESULTS: Plasma cortisol levels were not significantly decreased by treatment, while excretion of 11-deoxycortisol metabolites increased eightfold after 2 weeks indicating that concurrent hydrocortisone administration had not suppressed the adrenal. Ratios reflecting 11 beta-hydroxy/11-oxo metabolites of cortisol were significantly decreased, consistent with inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase (11-HSD). Other changes included significant decreases in the rates of 5 alpha vs 5 beta and of 20 alpha vs 20 beta reduction of corticosteroids. CONCLUSIONS: Metyrapone has multiple effects on extra-adrenal corticosteroid metabolism and is the only agent we know of which selectively inhibits 11-oxoreductase. Metyrapone thus provides a model for 11-HSD I deficiency and a tool for in-vitro studies of cortisol-cortisone interconversion. The results also suggest mechanisms whereby corticosteroid effects can be regulated separately from corticosteroid synthesis.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1975

The influence of metyrapone on the synthesis and release of prostaglandins from the pregnant rat uterus in vitro.

1 Metyrapone (150 mg/kg, s.c. or i.p.) an inhibitor of corticosteroid biosynthesis, significantly reduced the release of prostaglandins of the F-type from isolated preparations of pregnant rat uteri in vitro, on day 22 - the expected day of delivery. 2 Metyrapone and indomethacin administered in vitro both inhibited the conversion of 14C-arachidonic acid to prostaglandin E2 by homogenates of day 22 pregnant rat uteri. Metyrapone was approximately 150 times less potent than indomethacin. Although indomethacin also inhibited prostaglandin F2alpha production, metyrapone stimulated synthesis of this prostaglandin. The differential inhibition of prostaglandin synthesis by metyrapone may reflect sensitivity of the inhibitor to changes in experimental conditions. 3 Inhibition of prostaglandin synthesis may explain the effects of metyrapone on parturition in the rat.

Animals↗
PubMed1976

Evaluation of single oral dose metyrapone tests in children with hypopituitarism.

Evaluation of single-dose metyrapone tests in children with hypopituitarism; comparison with the prolonged metyrapone and insulin induced hypoglycaemia tests and their relationship with the etiology of hypopituitarism. Acta Paediatr Scand, 65:177, 1976.--Pituitary-adrenal reserve was evaluated in control and hypopituitary subjects by comparing the 8 a.m. plasma 11-deoxycorticoid response (11-DOCS) to a single midnight oral dose of metyrapone (short test) with 1) the 8 a.m. 11-DOCS increase under repeated oral doses of metyrapone (prolonged test) and 2) with the plasma corticoid response during arginine-insulin test. In the short and the prolonged metyrapone tests, the same response was obtained in 25 out of 27 patients. The short test was repeated in 22 patients and the 11-DOCS response did not show a significant difference. In 34 of 40 patients, the response to the short test was comparable to the response during the arginine-insulin test; only 3 patients with a normal 11-DOCS rise to the short test had a low response to insulin and vice versa. Among the low responders to the short test, the mean 11-DOCS value was significantly lower in subjects with operated craniopharyngiomas than in idiopathic hypopituitary patients (p less than 0.001). In the short test, the 8 a.m. baseline cortisol value was positively correlated with the 8 a.m. 11-DOCS response (p less than 0.001), the cortisol level allowing to predict the 11-DOCS response in 28 out of 53 patients. Thus, the short oral metyrapone stimulation was found to be a reliable test in hypopituitary children.

17-Hydroxycorticosteroids↗
PubMed1999

Diagnosis of ACTH deficiency. Comparison of overnight metyrapone test to either low-dose or high-dose ACTH test.

Test sensitivity and accuracy of 250 microg/m(2) ACTH test, 1 microg/m(2) ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.

Adolescent↗
PubMed1987

Late asthmatic response to Ascaris antigen challenge in dogs treated with metyrapone.

We developed an experimental dog preparation that shows a biphasic bronchoconstriction after allergen exposure. After anesthetization, the dogs were intubated with endotracheal tubes and manually ventilated. Respiratory resistance (Rrs) was measured by the forced oscillation method at 3 Hz. Ascaris suum, diluted from 10(-5) to 10(-2) of the extract, was inhaled during tidal breathing for 5 min. One hour before antigen challenge, 10 dogs received 70 mg/kg of metyrapone (cortisol synthesis inhibitor), and 2 h after antigen challenge 35 mg/kg of metyrapone were injected intravenously. In another 10 dogs, metyrapone was not administered. After the maximal increase in Rrs had been assessed (immediate asthmatic response), Rrs increased again 4 to 6 h after antigen challenge in 8 of the 10 dogs treated with metyrapone (late asthmatic response, 443 +/- 282% mean +/- SD of initial Rrs), which was significantly higher than Rrs 6 h after antigen challenge (124 +/- 41%) in dogs without metyrapone (p less than 0.01). In another 5 dogs, ragweed challenge with metyrapone caused no change in Rrs. Bronchoalveolar lavage at the time of the late response revealed a significant correlation between late asthmatic response and neutrophil accumulation (p less than 0.01) in all dogs. We conclude that cortisol depletion augments the occurrence of the late response. The present dog model may be a useful tool for study of the late response in bronchial asthma.

Airway Resistance↗